The disease "scabies" is a neglected worldwide health problem that is caused by the mite Sarcoptes scabiei that burrows in the stratum corneum of the skin. In the U.S., it occurs frequently in the general population and in institutions such as daycare centers and nursing homes. The prevalence is nearly 100% in infants and >50% in older children and women in some populations in the world. Scabies persists despite the availability of topical insecticides because the disease is transmitted before it is diagnosed and treated and significant resistance to insecticides has developed. The first time a person becomes infested with scabies the inflammatory/immune reaction in the skin is delayed for 4-8 weeks and there are no symptoms. The delay in the symptoms suggests that these mites may produce substances that can initially inhibit the host response. Previous studies have shown that mite extracts modulate the cytokine expression of keratinocytes, fibroblasts, monocytes, dendritic cells and lymphocytes. It appears that skin endothelial cells may play a key role in this delay of symptoms. A previous infestation with S. scabiei induces protective immunity. The mechanisms responsible for the delayed primary response and the protective immunity from a previous infestation are not understood. Our long term goal is to develop a better understanding of the host parasite relationship that will lead to development of novel strategies for the control/prevention and treatment of this disease. Prerequisites for development of new control and treatment strategies are to (1) elucidate key elements of the host's response by skin vascular endothelial cells that are responsible for delaying the inflammatory/immune reponses during a primary infestation, (2) isolate and immunobiochemically characterize S. scabiei molecules that modulate the host's inflammatory/immune response to scabies during the early stages of a primary infestation, and (3) determine the mechanism responsible for elimination of an infestation in hosts that express resistance to reinfestation. To accomplish Aim 1, we will determine the cytokine and adhesion molecule expression profiles of skin endothelial cells in response to scabies mite secretions or extracts. In Aim 2, we will use isoelectric focusing, SDS-PAGE and liquid chromatography to separate protein components of mite secretions and extracts and test isolated molecules for immunomodulating activity in several skin and blood cell types. For Aim 3, we will use electron microscopy and studies of mite biology in vivo to identify possible pathological and physiological reasons that mites are eliminated by resistant hosts.